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Update: Topical Antimicrobial Agents forChronic Wounds
C M E1 AMA PRA
Category 1 CreditTM
ANCC1.5 Contact Hours
R. Gary Sibbald, MD, DSc (Hons), MEd, BSc, FRCPC (Med)(Derm), FAAD, MAPWCA & Professor & Medicine and PublicHealth & University of Toronto & Toronto, Ontario, Canada & Director & International Interprofessional Wound Care Course &Masters of Science in Community Health (Prevention & Wound Care) & Dalla Lana Faculty of Public Health & University ofToronto & Past President & World Union of Wound Healing Societies & Clinical Editor & Advances in Skin & Wound Care &Philadelphia, Pennsylvania
James A. Elliott, MSc, BSc & Faculty & International Interprofessional Wound Care Course & Member & Wounds Canada ResearchCommittee & Trustee & T1International & Toronto, Ontario, Canada
Luvneet Verma, MAcc, BSc, MDc & Medical Student & University of Ottawa & Ottawa, Ontario, Canada
Alisa Brandon, MSc, BSc & Medical Student & University of Toronto & Toronto, Ontario, Canada
Reneeka Persaud, MD & Faculty & International Interprofessional Wound Care Course &Research Coordinator &WoundPedia &Canada
Elizabeth A. Ayello, PhD, RN, ACNS-BC, CWON, ETN, MAPWCA, FAAN & Faculty & Excelsior College School of Nursing &Albany, New York & President & Ayello Harris & Associates, Inc & Copake, New York & Clinical Editor & Advances in Skin &Wound Care & Philadelphia, Pennsylvania
The author, faculty, staff, and planners, including spouses/partners (if any), in any position to control the content of this CME activity have disclosed that they have no other financialrelationships with, or financial interests in, any commercial companies pertaining to this educational activity.
To earn CME credit, you must read the CME article and complete the quiz online, answering at least 13 of the 18 questions correctly.
This continuing educational activity will expire for physicians on October 31, 2018 and for nurses on October 31, 2019.
All tests are now online only; take the test at http://cme.lww.com for physicians and www.nursingcenter.com for nurses. Complete CE/CME information is on the last page of this article.
GENERAL PURPOSE:
To provide information on the use of topical antimicrobial agents for the treatment of chronic wounds.
TARGET AUDIENCE:
This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses
with an interest in skin and wound care.
OCTOBER 2017
C L I N I C A L M A N A G E M E N T
extra
ADVANCES IN SKIN & WOUND CARE & VOL. 30 NO. 10 438 WWW.WOUNDCAREJOURNAL.COM
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
LEARNING OBJECTIVES/OUTCOMES:
After participating in this educational activity, the participant should be better able to:
1. Examine features of wounds and wound healing as well as the purpose of specific antimicrobial agents.
2. Identify potential therapeutic and adverse effects of specific topical antimicrobial agents for the treatment of
chronic wounds.
ABSTRACT
Bacteria can delay or prevent healing in the surface compartmentof a chronic wound or invade the deep and surroundingstructures. This article focuses on the superficial compartmentand the appropriate use of topical antimicrobial therapies. Theauthors have reviewed the published evidence for the last 5 years(2012–2017) and extrapolated findings to clinical practice withcritical appraisal and synthesis of the recent literature with expertopinion, patient-centered concerns, and healthcare systemsperspectives. Summary evidence tables for commonly usedtopical antimicrobials are included.KEYWORDS: antimicrobial agents, iodine, polyhexamethylenebiguanide, silver, topical agents, wound healing
ADV SKIN WOUND CARE 2017;30:438–50.
INTRODUCTIONAs the population ages, chronic wounds represent an increased
burden to patients, healthcare professionals, and healthcare sys-
tems. These chronic wounds (present for >6–12 weeks) take longer
to heal than regular wounds and are often not treated effectively.
Worldwide, annual estimates of chronic wounds include 4.5 million
pressure injuries, 9.7 venous leg ulcers (VLUs; although there are
many other leg ulcer etiologies), and 10 million diabetic foot
ulcers. Diabetes incidence is growing worldwide, and healthcare
systems are going to be challenged to effectively manage diabetic
foot ulcers to prevent lower-limb amputations.
Critical colonization that can be treated topically and deep
and surrounding infections are complications of chronic wounds
that delay healing and increase associated healthcare costs.1
Wound-related bacterial damage occurs in the surface compart-
ment and can be treated topically; infections of the deep and
surrounding compartments require systemic treatment.
To help illustrate the difference between infection in the super-
ficial and deep tissue compartments, consider the analogy of a
thin layer of soup in a bowl. The bottom of the bowl is a con-
tinuous compartment, with the sides representing the deep and
surrounding compartments of a wound. The thin layer of soup
represents the superficial critical colonization and changes on the
wound surface that can be altered by topical therapy.
This article focuses on the superficial compartment and the
appropriate use of topical antimicrobial therapies. The authors
examined recent literature for the use of topical antimicrobials
in chronic wounds. Topical antibiotic agents popular in the past
such as mupirocin present several potential complications for
patients with chronic wounds including bacterial resistance with
a single mutation, contact allergy, inability to provide moisture
balance or moisture reduction, and the lack of autolytic debride-
ment. The last 40 years have seen the introduction of new classes
of antiseptic dressings for critically colonized wounds.
Wound Classification for HealabilityThe wound bed preparation paradigm provides a comprehen-
sive approach to chronic wound care that requires treatment of
the wound cause and addressing patient-centered concerns
(Figure 1).2
As part of the initial assessment, the ability of the wound to
heal needs to be determined (Table 1). Classification of the wound
as healable, maintenance, or nonhealable will impact the pro-
vider_s specific choices for local wound care including topical
antimicrobials and determining whether anti-inflammatory drugs
may be beneficial.
Most patients can have the wound cause corrected and have
adequate blood supply to heal (healable wound). However, not
all wounds are healable because of systems or patient limitations.
Patients may not be able to afford protective footwear or wear
them at all times. Similarly, a patient with a VLU may not wear
Figure 1.
WOUND BED PREPARATION PARADIGM 2015
B WoundPedia, reprinted with permission.
ADVANCES IN SKIN & WOUND CARE & OCTOBER 2017439WWW.WOUNDCAREJOURNAL.COM
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
compression bandages or be unable to afford compression
stockings to prevent recurrence.
With corrective interventions, a maintenance wound may
be reclassified as healable, or maintenance therapy will aim to
prevent wound deterioration. A patient with a major illness,
inadequate or uncorrectable vascular ischemia, or multiple co-
morbidities (eg, cancer, uncontrolled autoimmune disease, or
immunosuppressive drugs that may interfere with healing) can
render a wound nonhealable.
NERDSFive clinical signs, known as NERDS, can be used to identify
critical bacterial colonization. A validation study confirmed that a
wound possessing any 3 of the 5 NERDS criteria (73.3% sen-
sitive, 80.5% specific) would be an indication to prescribe a topical
antimicrobial agent (Figure 2).3
Each of the letters in the NERDS mnemonic represents a
clinical sign:
& Nonhealing is a measure of the length � width that did not
get smaller or increase in size over a 4-week period, indicating
that the proinflammatory environment on the wound surface
has prevented healing but that bacteria have not invaded the
sides of the wound.
& Exudate is increased as a sign of irritation on the surface of
the wound. The exudate may macerate the surrounding skin if
the dressing cannot handle the increased discharge.
& Red friable tissue on the wound surface indicates that vascular
endothelial growth factor will produce more blood vessels than
needed for mature granulation tissue. This is often bacterially
stimulated and leads to a loose exuberant granulation tissue that
may rise above the wound surface and will leave a blood stain
when a dressing is removed. This tissue is different from firm
pink granulation at a level surface with the wound edge that
would promote re-epithelialization.
& Debris on the wound surface (often yellow, brown, or black
loose slough) is a result of surface cell death from local hostile
conditions for viable cell growth and proliferation.
& Smell is the result of proliferation of gram-negative bacteria
and anaerobes.
STONEESBy a similar analogy, a wound that presents with any 3 of the 7
STONEES criteria indicates the potential need for systemic therapy.
Four of these criteria come from the marginal surface of the wound:
Size is increasing,
Table 1.
WOUND HEALABILITY, DEBRIDEMENT, INFLAMMATION/INFECTION MANAGEMENT, AND MOISTURE BALANCE
Wound Healability Classification Debridement Inflammation/Infection Management Moisture Management
Healable
Adequate blood supply; can
correct the cause
Active Treat inflammation/infection (topically or
systemic) including antisepsis as required
Moisture balance
Maintenance
Patient or healthcare system
factors prevent healing
Conservative (no disruption of
surface blood vessels or bleeding)
Bacterial reductionVantisepsis Moisture reduction
Nonhealable
Noncorrectable cause or lack
of blood supply
Comfort Bacterial reductionVantisepsis Moisture reduction
Figure 2.
THE CONCEPT OF NERDS AND STONEES SUPERFICIAL
CRITICAL COLONIZATION VERSUS DEEP AND
SURROUNDING INFECTION
B WoundPedia, reprinted with permission.
ADVANCES IN SKIN & WOUND CARE & VOL. 30 NO. 10 440 WWW.WOUNDCAREJOURNAL.COM
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Temperature of the surrounding skin by infrared thermom-
etry is greater than 3-F compared with the same area on the
opposite side of the patient_s body,4
Os is the Latin word for boneVprobing or expositedVand in-
creased Exudate or Smell as outlined above in the NERDS criteria.
New areas of breakdown with small satellite areas of break-
down in the wound margins, and
Erythema (often difficult to determine in brown or black skin)
and/or
Edema of the surrounding skin (otherwise known as cellulitis).
Three criteria are derived from the deep wound compartment:
New or localized wound-related pain is an additional symptom
that acts as supporting evidence to the clinical signs criteria for
critical colonization or deep and surrounding infection.
RECENT LITERATURE ON TOPICALANTIMICROBIAL DRESSINGSThe authors searched MEDLINE (PubMed), the Cochrane Li-
brary, University of York Centre for Reviews and Dissemination
database, and Google Scholar for systematic reviews, health tech-
nology assessments, high-quality randomized controlled trials
(RCTs), and narrative review articles published from January 2012
to June 2017. Hand referencing was utilized. Burn, acute, trau-
matic, and postsurgical wound literature was excluded from this
review. For topical antimicrobial therapies, where no high-quality
studies could be found, lower-quality evidence was used to sup-
plement findings along with expert knowledge. Search strings
used are outlined in Table 2. This search was supplemented by
landmark articles as per author judgment and a process similar to
guideline synthesis.
TOPICAL ANTIMICROBIALS FOR HEALABLEWOUNDSThe following sections will discuss categories of topical anti-
microbial therapies. Particular attention will be given to chemical
composition, form, function, and clinical application. When there
is not high-quality (RCT) evidence for an agent, this will be stated;
however, the Cochrane reviews advise that Bthe lack of reliable
evidence means that it is not possible to recommend discontin-
uation of any of the agents reviewed.[ Based on this, the authors
have indicated the current logical best practices for each of the
following commonly used topical antimicrobial agents: poly-
hexamethylene biguanide (PHMB), silver, iodine, methylene
blue/crystal violet (MB/CV), and honey.
Polyhexamethylene BiguanideIn wound dressings, PHMB is a positively charged polymer with
a hydrophobic backbone and cationic groups separated by hexa-
methylene chains.5 This structure allows PHMB to bind to the
negatively charged bacterial cell wall. When PHMB attaches to
the acid membrane elements of the bacteria, the bacteria sub-
sequently lose fluidity, causing separation of the individual mem-
brane lipids and dissolution of the bacterial cell. This bactericidal
mechanism means there are no residual organisms left alive to
facilitate resistance.
Polyhexamethylene biguanide has been combined in gauze
and foam dressing formats. Polyhexamethylene biguanide foam
dressings are best utilized for healable surface wounds with
exudate. Polyhexamethylene biguanide gauze packing is appro-
priate for a deep exudative wound that would benefit from anti-
bacterial action. These dressings do not release the PHMB; rather,
bacteria are killed in the compartment above the wound in the
dressings. The effect is microbicidal for a broad spectrum of
bacteria, yeast, and viruses.
One high-quality systematic review by Canadian authors6
supports PHMB use in chronic wounds. A recent low-quality
narrative review covers practical advice, suggesting that while
PHMB is effective in preventing critical wound colonization it
may not be effective in destroying the biofilm of colonized
wounds.7
In a 4-week, 45-patient RCT, a nonrelease PHMB foam was
compared with foam alone. Surrogate outcomes favored the
use of PHMB foam.5 The PHMB foam dressing was a signifi-
cant predictor of reduced wound superficial bacterial burden
(P = .016) at week 4 as compared with the foam alone. Pain
reduction was also statistically significant at week 2 (P = .0006)
and at week 4 (P = .02) in the intervention group. Polymicrobial
organisms were recovered at week 4 in 5.3% of the PHMB foam
dressing group patients versus 33% in the control group (P =
.04). Subjects randomized to the PHMB foam dressing also had a
35% median reduction in wound size by week 4, compared with
28% in the control group, but this result did not reach statistical
significance because of the small sample size of patients.
Additional supporting evidence is tabulated in Table 3.
SilverSilver is ideally suited to healable wounds with critical coloni-
zation. It is an antibacterial agent in an ionized form that
requires an aqueous environment. Ionized silver can attack at
least 3 cellular components: cell membranes, cytoplasmic organ-
elles, and DNA, so resistance is uncommon. Silver is most often
combined with calcium alginates, hydrofibers, foams, and hydrogels
and used as a coating on mesh-type structures with the appro-
priate moisture balance chosen for sustained release and exudate
management to avoid periwound maceration. Topical silver can
be combined with foam dressings so that the ionized silver can
be released slowly in response to wound exudate. For nonheal-
able or maintenance wounds where moisture reduction is the
ADVANCES IN SKIN & WOUND CARE & OCTOBER 2017441WWW.WOUNDCAREJOURNAL.COM
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Table 2.
SEARCH STRINGS UTILIZED
Polyhexamethylene biguanide
Cochrane Library: polyhexamethylene biguanide
University of York Centre for Reviews and Dissemination: polyhexamethylene biguanide
PubMed: BWounds and Injuries[[MeSH] AND Bpolyhexamethylene biguanide[ + Bwound[ AND Bpolyhexamethylene biguanide[
Silver
University of York: (Bsilver[) Limit 2014-2017, Canadian and International HTAs
Cochrane Library: (Bsilver[) Limit = 2014–2017
Google Scholar: wound and silver and topical
PubMed: BWounds and Injuries[[MeSH] and Bsilver[ and Btopical[ Sort by: Relevance Filters: Publication date from 2014/01/01; humans; English
Also included articles from an earlier search strategy:
Cochrane Library: (Btopical antibiotic[ AND Bwound[) AND (Btopical[ AND Bantimicrobial[ AND Bwound[) AND (Btopical[ AND Bantibiotic[
AND Bwound[)
YORK CRT: ((antibiotic AND topical AND wound)) and ((Systematic review:ZDT and Bibliographic:ZPS) OR (Systematic review:ZDT and
Abstract:ZPS) OR (Cochrane review:ZDT) OR (Cochrane related review record:ZDT) OR (Economic evaluation:ZDT and
Bibliographic:ZPS) OR (Economic evaluation:ZDT and Abstract:ZPS) OR Project record:ZDT OR Full publication record:ZDT) IN DARE,
NHSEED, HTA FROM 2005 TO 2014
PubMed: ((BAnti-Bacterial Agents[[MeSH]) AND BWounds and Injuries[[MeSH]) AND BAdministration, Topical[[MeSH]))
Google Scholar: (Btopical antibiotic[ AND Bwound care[) AND (Btopical antibiotic[ AND Bwound care[ AND Bacute[)
Honey
University of York: topical OR superficial OR epidermal OR critical AND colonization OR biofilm AND honey
PubMed: BWounds and Injuries[[MeSH] AND honey (2014-; English, human)
topical OR superficial OR epidermal OR critical AND colonization OR biofilm AND honey (2014-; English, human)
Google Scholar: topical OR superficial OR epidermal OR critical AND colonization OR biofilm AND honey (2014-) sorted by relevance
(went up to page 7 (including page 7))
Chlorhexidine
University of York: (Bchlorhexidine[) Limit 2014-2017
Cochrane Library: (Bchlorhexidine[) Limit = 2014-2017
Google Scholar: Bwound and chlorhexidine[ Limit = 2014-2017, exclude patents and citations
PubMed: BChlorhexidine[[MeSH] AND BWounds and Injuries[[MeSH] AND ((B2014/01/01[[PDAT] : B3000/12/31[[PDAT]) AND
Bhumans[[MeSH Terms] AND English[lang])
Methylene Blue/Crystal Violet
University of York: (Bmethylene blue[) Limit 2014-2017
(Bgentian violet[) Limit 2014-2017
Cochrane Library: (Bmethylene blue[) Limit = 2014-2017
(Bgentian violet[) Limit = 2014-2017
Google Scholar: Bwound and methylene blue[ Limit = 2014-2017, exclude patents and citations
Bwound and gentian violet[ Limit = 2014-2017, exclude patents and citations
PubMed: BWounds and Injuries[[MeSH] AND BMethylene Blue[[MeSH] AND ((B2014/01/01[[PDAT] : B3000/12/31[[PDAT]) AND
Bhumans[[MeSH Terms] AND English[lang])
BWounds and Injuries[[MeSH] AND BGentian Violet[[MeSH] AND ((B2014/01/01[[PDAT] : B3000/12/31[[PDAT]) AND Bhumans[[MeSH
Terms] AND English[lang])
Iodine
University of York: topical OR superficial OR epidermal OR Bcritical colonization[ OR biofilm AND iodine
Pubmed: BWounds and Injuries[[MeSH] AND iodine (2014-; English, human)
topical OR superficial OR epidermal OR Bcritical colonization[ OR biofilm AND iodine (2014-; English, human)
Google Scholar: topical OR superficial OR epidermal OR Bcritical colonization[ OR biofilm AND iodine (2014-) sorted by relevance (went
up to page 7 (including page 7))
ADVANCES IN SKIN & WOUND CARE & VOL. 30 NO. 10 442 WWW.WOUNDCAREJOURNAL.COM
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
target, silver is not indicated because silver cannot remain in an
ionized state on a dry surface.2
Topical silver dressing studies were extensively reviewed by
Leaper9 in an international consensus published in 2012, which
concluded that silver dressings may be effective at reducing
bacterial burden in critically colonized wounds.
Munter et al10 reported surrogate wound outcomes in a 4-week
trial of 619 patients comparing silver foam versus local best prac-
tices. The silver foam had a significantly higher median reduction
in ulcer area compared with the control group (47.1% vs 31.8%;
P = .0019). The silver group also had significantly improved
(P <.05) exudate handling, ease of use, odor reduction, and
pain control.
Carter et al11 in 2010 conducted a systematic review of 10 leg
ulcer RCTs with 38 to 619 patients in each of the studies. This review
found some evidence that silver-impregnated dressings improved
the short-term healing of leg ulcers, especially in the first 4 weeks;
however, the longer-term effectiveness requires more study.
The more recent publications on silver as a topical antimicro-
bial agent, summarized in Table 4, emphasize the gaps in current
knowledge and the need for further studies. There are also recom-
mendations for decision makers that cost-effectiveness and pa-
tient preference should be key elements for dressing selection.
IodineIodine is a natural, nonmetallic element that is essential for the
production of thyroid hormone. Iodine has several antimicrobial
actions including blocking bacterial cell efflux pumps, interfering
with cellular respiratory processes, changing DNA structure, and
denaturing cellular proteins and enzymes. Patients on iodine for
large wounds or extended periods should have thyroid function
tests at regular intervals as hypothyroidism or hyperthyroidism
can be induced by iodine wound dressings.2
Iodophors, developed in the 1950s, are safer, slow-release
iodine delivery systems.18 The 2 most commonly used iodophors
in modern wound dressings are povidone iodine (PVP-I) and
cadexomer iodine. Povidone iodine is a chemical complex of
polyvinylpyrrolidone and elemental iodine. It is available as a
slow-release dressing (knitted viscose mesh) in some regions
(eg, Canada and Europe), along with 7.5% to 10% solution
formats, creams, ointments, and sprays. Cadexomer iodine is
an absorptive polysaccharide that absorbs exudate and provides
Table 3.
RECENT EVIDENCE ON POLYHEXAMETHYLENE BIGUANIDE TOPICAL DRESSINGS
PHMB foam may be used for healable wounds with exudate; PHMB gauze and packing may be used for healable, nonhealable, and maintenance woundswith exudate. PHMB foam dressings may reduce wound size, decrease bacterial count, and decrease pain in wounds with superficial bacterial burden.
Study Findings Conclusions
To et al6
A 2016 systematic review of
English-language RCTs covering
publications between 1946 and
February 2014 on the
effectiveness of topical PHMB for
the treatment of chronic wounds
& 6 of 1,725 articles met inclusion criteria
& 3 single-center trials and 3 multicenter trials
& Sample sizes ranged from 10 to 40 adult
chronic wound participants
& 2 studies: BPHMB dressings achieved
a faster, more substantial reduction in
bacteria count[6
& 2 studies had a reduction in the number
of polymicrobial organisms
& 2 studies: PHMB dressings eradicated
MRSAfrom pressure ulcer tracheostomysites
& 4 studies demonstrated pain reduction
from the use of PHMB agents
BThe existing evidence shows that topical
PHMB may promote healing of chronic stalled
wounds, reduce bacterial burden, eliminate
methicillin-resistant Staphylococcus aureus,
and alleviate wound-related pain.[6
Hurlow7
A narrative 2017 review on the
benefits of PHMB in wound care
& Reviewed in vitro and in vivo studies
& Cites MRSA growth suppression effect
of PHMB by Kirker et al8
& Cautions toxicity may be an issue in
some patients if PHMB is used alone
BPHMB-impregnated dressings appear to be
very effective as a barrier to wound colonization
and infection.[7
Abbreviations: MRSA, methicillin-resistant Staphylococcus aureus; PHMB, polyhexamethylene biguanide; RCTs, randomized controlled trials.
ADVANCES IN SKIN & WOUND CARE & OCTOBER 2017443WWW.WOUNDCAREJOURNAL.COM
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Table 4.
RECENT EVIDENCE ON SILVER-BASED DRESSINGS
This table covers silver dressings indicated for healable wounds with critical colonization. Cochrane Reviews, systematic reviews, and RCTs werereviewed to evaluate current evidence regarding the use of silver as a topical treatment for wounds. Highly-quality Cochrane Reviews found uncertainevidence for the use of silver-based dressings for a variety of wounds including surgical, pressure, and venous ulcers and fungating wounds.
Study Findings Conclusions
O_Meara et al12
This updated Cochrane Review
conducted in 2014 included 45 RCTs of
4,486 participants on antibiotics and
antiseptics for VLUs.
& Examined silver- and antibiotic-containing
ointments (12 RCTs)
& Silver-based products: no difference in
healing with silver sulfadiazine or when
different brands of silver-impregnated
dressings compared with nonantimicrobial
dressings or honey in promoting healing
of VLUs
BLack of reliable evidence means that
is it not possible to recommend the
discontinuation of any of the agents
reviewed.[12
BCurrent evidence does not support
the routine use of honey- or silver-based
products.[12
Leaper13
This 2011 editorial provides expert
opinion and gives context to recent
evidence, especially some of the
difficulties with current research and
reliance on only RCT meta-analysis/
Cochrane Reviews.
& Use of topical antimicrobials, specifically
antiseptics (eg, silver) rather than antibiotics,
should be supported because of
(1) reduction in the risk of critical colonization
(2) refuting antimicrobial resistance
(3) reduction in the risk of biofilm formation
(4) aiding debridement
(5) preparing the wound bed
(6) infection prevention
B[The] rise of antibiotic-resistant organisms,
especially methicillin-resistant
Staphylococcus infection (MRSI), is a
major reason to revisit use of topical
antimicrobials.[13
Adderley and Holt14
This is the third updated Cochrane
Review (2014) on topical agents and
dressing on fungating wounds.
& 4 RCTs (164 people) with 2 involving
silver dressings
& More patients had decreased malodor
in the foam dressing and silver group
than in the foam dressing without silver
group (P = .049).
& No statistically significant difference
with regard to exudate, malodor, and
wound pain for manuka honey–coated
dressings than with nanocrystalline
silver-coated dressings.
& Weak evidence to suggest that foam
dressings containing silver may be
effective in reducing malodor
BInsufficient evidence in this review to
give a clear direction for practice with
regard to improving quality of life or
wound symptoms in associated with
fungating wounds.[14
Dumville et al15
A Cochrane Review in 2014 (29 RCTs) on
dressings for the prevention of SSI,
including silver-containing dressings
following clean and potentially
contaminated surgery
& A relative risk of 1.11 of SSI for
silver-containing dressings vs basic
wound contact dressing for clean
surgery. Grade: very low-certainty
evidence
& A relative risk of 0.83 of SSI for
silver-containing dressings vs basic
wound contact dressing for potentially
contaminated surgery. Grade: very
low-certainty evidence
BIt is uncertain whether covering surgical
wounds healing by primary intention with
wound dressings reduces the risk of SSI,
or whether any particular wound
dressing is more effective than others in
reducing the risk of SSI, improving
scarring, reducing pain, improving
acceptability to patients, or is easier to
remove. Most studies in this review were
small and at a high or unclear risk of
biasI. Based on the current evidence,
decision makers may wish to base
decisions about how to dress a wound
following surgery on dressing costs as
well as patient preference.[15
(continues)
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autolytic debridement along with a slow release of iodine into the
wound bed.18
In a recent review of iodine, the following concluding state-
ment summarized the literature review19:
BAlthough it has been speculated that iodine delays healing
and is cytotoxic, there is substantial evidence to suggest that
the commonly used low-concentration, slow-release iodophors
improve healing rates and are effective as highly potent antimi-
crobials with a broad spectrum of activity, including antibiotic-resistant
strains such as MRSA [methicillin-resistant Staphylococcus aureus].
It is unfortunate that the concerns about iodine are based on
studies that are so varied in method and design that it is difficult
to draw reliable comparisons and conclusionsI. but it is now
widely accepted that slow-releasing iodophor antimicrobials are
safe and have minimal detrimental impact on wound healing.[
The recent evidence summarized in Table 5 adds further sup-
port for cadexomer iodine for the improved healing of VLUs and
the utility of PVP-I for nonhealable or maintenance wounds.
Table 4.
RECENT EVIDENCE ON SILVER-BASED DRESSINGS, CONTINUED
This table covers silver dressings indicated for healable wounds with critical colonization. Cochrane Reviews, systematic reviews, and RCTs werereviewed to evaluate current evidence regarding the use of silver as a topical treatment for wounds. Highly-quality Cochrane Reviews found uncertainevidence for the use of silver-based dressings for a variety of wounds including surgical, pressure, and venous ulcers and fungating wounds.
Study Findings Conclusions
Norman et al16
A Cochrane Review in 2016 (12 RCTs
of 576 participants) on antibiotics and
antiseptics for Stage Q2 pressure ulcers
& Povidone iodine vs silver sulfadiazine: 63.6%
of ulcers treated with povidone iodine were
judged to be free of infection compared with
100% ulcers treated with silver sulfadiazine.
Grade: low-quality evidence
& Silver mesh vs silver sulfadiazine: no
complications as a result of treatment in either
group; 34.6% reduction in mean ulcer area in
the silver mesh group compared with 20.1% in
the silver sulfadiazine group. Mean costs were
$263 for silver mesh vs $1,812 for silver
sulfadiazine.
& Silver alginate vs silver sulfadiazine: 44.27%
reduction in mean ulcer area in the silver
alginate group compared with 51.07% in the
silver sulfadiazine group. Mean costs were
$377 for silver alginate vs $467 for silver
sulfadiazine.
& Silver sulfadiazine vs saline: 78.6% of ulcers
treated with saline were free of infection
compared with 100% ulcers treated with silver
sulfadiazine. Grade: low-quality evidence
BThe relative effects of systemic and
topical antimicrobial treatments on
pressure ulcers are not clear. Where
differences in wound healing were
found, these sometimes favored the
comparator treatment without
antimicrobial properties.[16
Tricco et al17
A systematic review in 2015 that
examined effective interventions to
treat complex wounds, including
silver dressings for unspecified mixed
complex wounds
& One meta-analysis supported that Btopical
silver and silver dressings were found more
effective than placebo or conservative
wound care or nonsilver therapies,[ and
BSilver-impregnated dressings were more
effective than dressings not containing silver
in a meta-analysis.[
& For mixed complex wounds, silver dressings
were found to be more effective than no
treatment.
BOur results confirm that there are
numerous interventions that can be
utilized for patients with complex
wounds. However, few treatments
were consistently effective
throughout the literature.[17
Abbreviations: RCTs, randomized controlled trials; SSI, surgical site infection; VLUs, venous leg ulcers.
ADVANCES IN SKIN & WOUND CARE & OCTOBER 2017445WWW.WOUNDCAREJOURNAL.COM
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Table 5.
RECENT EVIDENCE ON IODINE
Iodine (especially cadexomer iodine) can be used for healable wounds; nonhealable and maintenance wounds may benefit from PVP-I, especially indelayed-release format. There is high-quality evidence in the form of a Cochrane Review and a JAMA clinical evidence synopsis on the utility ofusing cadexomer iodine in the treatment of venous leg ulcers.
12,20 In addition, there is evidence in the form of a retrospective chart audit that PVP-I maybe efficacious in the treatment of diverse maintenance and nonhealable ulcers.21
Study Findings Conclusions
O_Meara et al12
A Cochrane Review in 2014 that
summarized the research on various
antibiotics and antiseptics in promoting
the healing of VLUs
& Analysis of 11 RCTs on cadexomer
iodine vs standard care found that more
VLUs healed with cadexomer iodine vs
standard care by 4-12 wk.
& Analysis of 6 RCTs on PVP-I found that
there was no difference in complete
healing when PVP-I was compared with
hydrocolloid, moist wound healing
dressings, or foam dressings according
to wound status.
This Cochrane Review suggests that
some evidence supports the use of
cadexomer iodine (but not PVP-I)
to improve healing of VLUs over
standard care.
O_Meara et al20
A clinical evidence synopsis published
by O_Meara, Richardson, and Lipsky in
JAMA in 2014 on treatments of VLUs
& 4 pooled RCTs (212 patients) suggest
that cadexomer iodine was associated
with better healing rates but more adverse
events (such as pain and itching) than
standard care: BSingle RCTs demonstrated
no association with better healing for
cadexomer iodine compared with silver
dressings; PVP-I compared with usual
care, or mupirocin compared with
placebo.[20
This JAMA clinical evidence synopsis
suggests that treatment with cadexomer
iodine may be associated with improved
healing rates for VLUs but more adverse
events as compared with standard care.
Woo21
A retrospective chart audit in 2014 on
the efficaciousness of PVP-I in the
management of maintenance or
nonhealable wounds
& Charts from 30 patients from a Canadian
Wound Clinic with a total of 42 wounds
were reviewed
& All wounds were treated with topical
PVP-I for 6 mo with monthly monitoring.
& 28.6% of wounds (n = 12) completely
closed and 45.2 % (n = 19) of wounds
decreased in size at the 6-mo mark
& Some transient burning of stinging and
documented cases of irritant and potential
allergic dermatitis
Use of PVP-I for maintenance of
nonhealable ulcers decreased wound size
in 73% of wounds over a 6-mo period.
Norman et al22
This Cochrane Review in 2016
summarized 11 RCTs of 886 participants
comparing various antibiotics and
antiseptics for promoting healing of
surgical wounds by secondary intention
& In 2 studies, iodine preparation vs no
antiseptic treatment to promote healing
by secondary intention
& No clear evidence could be found to
support one treatment over the other
BThere is no robust evidence on the relative
effectiveness of any antiseptic/antibiotic/
antibacterial preparation evaluated to date
for use on surgical wounds healing by
secondary intention.[22
Abbreviations: PVP-I, povidone iodine; RCTs, randomized controlled trials; VLUs, venous leg ulcers.
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Methylene Blue and Crystal Violet FoamDressingsThis product is a relatively nonrelease foam dressing with 2 agents,
MB and CV, which produce a redox (oxidation-reduction) envi-
ronment inhibiting the growth and survival of bacteria. There are
2 foam formats. The original polyvinyl alcohol foam needs to be
partially hydrated to bind surface slough and provide autolytic
debridement. The foam structure facilitates wicking and moisture
retention/moisture balance. The more traditional polyurethane
dressing is similar to most other foam products in its fluid-
handling characteristics without autolytic debridement.2
Recent evidence on MB/CV is outlined in Table 6.
HoneyHoney has been used in wound care for centuries because of
its antibacterial and anti-inflammatory properties. Its acidic pH
(3.2–4.5) and high sugar content (osmolality) make the local wound
environment hostile to bacteria. Hydrogen peroxide released by
honey is antibacterial; however, this action can be neutralized by
blood, serum, and wound exudate. Manuka trees and some other
Leptospermum genus plants have bee-derived honey that also
contains methylglyoxal, an additional and more stable antimi-
crobial component. Honey may lose its antibacterial action when
diluted with wound exudate, but this may not increase the
incidence of bacterial resistance.2
Medical-grade honey should be used instead of honey from
food sources. This is because bacterial spores, including Clos-
tridium species, can persist in honey and have the potential to
cause disease if activated.
Recent literature is summarized in Table 7. The following
quote best summarizes the evidence on the use of honey in
chronic wounds: BCurrent evidence does not support the
routine use of honey. However, the lack of reliable evidence
means that it is not possible to recommend the discontinuation of
any of the agents reviewed.[12
There may still be a role for honey in specialized patients
where autolytic debridement is required for hard, fibrous
surfaces or in wounds that need an increased moisture
content.25
WOUND-PACKING MATERIALSWound-packing materials are required for deeper wounds (eg,
Stages 3 and 4 pressure injuries). When packing a wound, clin-
icians need to match form to function. The packing materials
listed in Table 8 are related to their key properties. Dry gauze will
absorb exudate, but it is not antibacterial, and bacteria can grow
Table 6.
RECENT EVIDENCE ON METHYLENE BLUE AND CRYSTAL VIOLET
These dressings are suitable for antibacterial action above the wound surface. They are indicated for exudating wounds with critical colonization andachieving moisture balance. The PVA foam provides autolytic debridement. Two case series
23,24 found that the use of methylene blue and gentianviolet dressings may be suitable for managing diverse chronic wounds. Both case series found that patients had fewer signs and symptoms of woundinfection and decreased wound size.
Study Findings Conclusions
Coutts et al23
A nonrandomized case series of
15 patients (8 DFUs and 7 leg ulcers)
evaluating antibacterial dressing made
of PVA foam bound with gentian violet
and methylene blue as well as compression
for venous leg ulcers and offloading
devices for DFUs
& 47% of patients had a decrease
in NERDS signs at the end of the
study period
& Improvements in the pain score were
noted in some patients (38% reported a
decrease in pain), and decrease in wound
size was also noted in 57% of patients
& An antibacterial foam dressing consisting
of PVA foam bound with gentian violet and
methylene blue Bshowed encouraging
results and may be a suitable option
for lower-extremity chronic wounds
demonstrating an increased superficial
bacterial burden.[23
& The antibacterial foam also appears to
provide autolytic debridement.
Woo and Heil24
A prospective, nonrandomized case
series based on 29 Canadian patients with
chronic wounds exhibiting signs of local
infection. Wounds were managed with
antibacterial foam dressing containing
methylene blue and gentian violet.
& At week 4, wound surface area was
reduced by an average of 42.5%
(21.4–12.3 cm2), and wounds went from
an average of 3.6 wound infection signs
and symptoms to 0.9.
Foam dressings containing methylene
blue and gentian violet may be efficacious
in improving healing and reducing signs
and symptoms of wound infection.
Abbreviations: DFUs, diabetic foot ulcers; PVA, polyvinyl alcohol; RCTs, randomized controlled trials.
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in the gauze and contaminate the wound surface. Moist saline
gauze will donate moisture to the wound surface, but again, it is
not antibacterial and may facilitate wound contamination. With
low host resistance, contamination can lead to critical coloniza-
tion, then potential deep and surrounding infection.
Both PHMB gauze and iodine-saturated ribbon gauze are
antibacterial. The PHMB gauze will sterilize the compartment
above the wound by killing bacteria that penetrate the gauze.
This mechanism relies on host resistance to clear the bacteria
on the wound surface with a decreased number of contam-
inating organisms. Iodine-saturated ribbon gauze will deliver
iodine to the surface of the wound, as long as there is an orange
color in the gauze. There is probably less toxicity from PVP-I on
the wound surface than predicted by in vitro studies.19 As soon as
critical colonization is reversed, PHMB ribbon gauze may pre-
vent surface bacterial contamination and relies on host resistance
to prevent the return of critical colonization.
TOPICAL ANTISEPTIC AGENTSTopical antiseptic agents are often used in maintenance and
nonhealable wounds where tissue toxicity may not be as im-
portant as the agents_ antibacterial properties.
Chlorhexidine is related to PHMB and is available in antiseptic
preparation solutions for the operating room or minor surgeries;
mouthwash formulations with aqueous bases that will not burn
or sting open skin; and petrolatum-type tulle dressings that have
a nonrelease format to minimize bacteria in the compartment
above the wound.
Polyhexamethylene biguanide is often used as a preservative
in eye and ear preparations, which adds indirect evidence to its
Table 7.
RECENT EVIDENCE ON HONEY
Honey is indicated for hard, firm eschars, and selected cases of critically colonized wounds. There is currently little evidence to support the use of honeydressings for chronic wounds. A recent Cochrane Review found no benefit in using honey dressings for VLUs.
12 Furthermore, while a case-controlstudy26 found no difference in healing of bedsores with the use of honey dressings versus povidone iodine, this is not sufficient evidence to recommendthe routine use of honey dressings.
Study Findings Conclusions
Khadanga et al26
A low-quality descriptive, case-control
study published in 2015 at 1 tertiary heath
center in India conducted over 1 y (N = 40
persons aged Q15 y) on the use of honey vs
povidone iodine in patients with bedsores
& Patients in the honey group reported
significantly less pain by day 10 (as
measured by the visual analog scale).
The decrease in the size of the wounds
between the 2 groups was not statistically
significant, and the bacterial load by day
10 was similar in both groups.
Decrease in wound size and bacterial
burden at day 10 was similar between
povidone iodine and honey.
O_Meara et al12
An updated Cochrane Review in 2014
that included 45 RCTs of 4486
participants on antibiotics and
antiseptics for VLUs.
& 2 RCTs were reported on honey
products and found no difference in time
to healing or complete healing between
wounds treated with honey products vs
usual care.
BCurrent evidence does not support the
routine use of honey. However, the lack of
reliable evidence means that it is not
possible to recommend the discontinuation
of any of the agents reviewed.[12
Abbreviations: RCTs, randomized controlled trials; VLUs, venous leg ulcers.
Table 8.
THE PROPERTIES OF COMMON WOUND-PACKING
MATERIALS
Wound-Packing Material Properties
Dry gauze Absorbs exudate
Not antibacterial
Moist saline gauze Donates moisture and
hydrates wound
Not antibacterial
PHMB gauze Absorbs exudate
Provides antibacterial activity
above the wound
Nonrelease, no tissue toxicity
Povidone iodine–soaked gauze Iodine delivered to the wound
surface
Penetrates biofilm and decreases
surface bacteria
Some potential tissue toxicity
Abbreviation: PHMB, polyhexamethylene biguanide.
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low toxicity. It is a large molecule, so percutaneous penetra-
tion is minimal.
Povidone iodine may also be used to paint around the edge
of a maintenance wound or an area of gangrene. The infection
of the deep and surrounding tissue will usually begin at the
proximal edge of the gangrene, and this is where it is more
important to paint the PVP-I to minimize bacterial invasion.
Compresses with diluted acetic acid (0.5%–1%) can lower
wound pH and create a hostile environment for Pseudomonas and
other bacteria that prefer an alkaline environment. Pseudomonas
can often be treated topically, preferably with 2 agents (eg, acetic
acid compresses and PVP-I or cadexomer iodine). If gram-positive
and other bacteria are treated systemically, it is often not necessary
to use oral agents against Pseudomonas, even for diabetic neuro-
trophic foot infections.27 More recently, hypochlorous acid has
been utilized in some clinics in a similar fashion.
Other antiseptic agents in the red categories of Figure 3
have higher tissue toxicity and are not currently recommended
for routine use in chronic wounds.
CONCLUSIONSTopical antiseptic agents are recommended for critically col-
onized chronic wounds. Patients should be carefully monitored
every 2 to 4 weeks, and if the critical colonization persists, deep
and surrounding infection, inadequate treatment of the cause, or
patient-centered concerns should be reassessed. For all wounds,
cleansing with agents that lower surface pH (into the acidic
range) may aid in bacterial reduction, especially for gram-negative
bacteria including Pseudomonas.
For healable wounds, moisture balance can be complemented
with local care for critical colonization. Clinical options include
silver dressings, slow-release iodine, medical-grade manuka honey,
nonrelease PHMB, or MB/CV dressings. Additional criteria for
dressing selection may be based on formulary availability, cost-
effectiveness, and patient preference.
Nonhealable or maintenance wounds are best served with
moisture reduction and topical antiseptics that may include PVP-I
or chlorhexidine (or its derivative PHMB). Each patient must be
considered individually, and wounds assessed for pain, local
wound fragility, and tissue viability in order to make the best
choice for local wound care utilizing the wound bed prepara-
tion paradigm.
PRACTICE PEARLS
Figure 3.
SELECT ANTISEPTIC AGENTS LISTED BY INCREASING CYTOTOXICITY
NB: Agents are color-coded by safety profile and antiseptic action. Green = low toxicity potential; yellow = no antibacterial effect; red = high toxicity potential.
& Topical antimicrobial use should be based on 3 or more
NERDS signs.
& Silver is anti-inflammatory but needs an aqueous base, not
a dry environment.
& Iodine is effective in aqueous and dry environments and
penetrates biofilms because of its proinflammatory properties.
& Polyhexamethylene biguanide is a nonrelease antimicrobial
agent that provides bacterial action above, but not on the
surface of, wounds.
& Honey is antibacterial and provides oncolytic debridement,
but more evidence is required to support routine chronic
wound usage.
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REFERENCES1. Driscoll P. Wound prevalence and wound management, 2012-2020. MedMarket Diligence.
2013. http://blog.mediligence.com/2013/01/29/wound-prevalence-and-wound-management-
2012-2020. Accessed July 25, 2015.
2. Sibbald RG, Elliott JA, Ayello EA, Somayaji R. Optimizing the moisture management tightrope
with wound bed preparation 2015B. Adv Skin Wound Care 2015;28:466-76.
3. Woo KY, Sibbald RG. A cross-sectional validation study of using NERDS and STONEES
to assess bacterial burden. Ostomy Wound Manage 2009;55(8):40-8.
4. Sibbald RG, Mufti A, Armstrong DG. Infrared skin thermometry: an underutilized cost-
effective tool for routine wound care practice and patient high-risk diabetic foot self-
monitoring. Adv Skin Wound Care 2015;28:37-44.
5. Sibbald R, Coutts P, Woo K. Reduction of bacterial burden and pain in chronic wounds
using a new polyhexamethylene biguanide antimicrobial foam dressingVclinical trial
results. Adv Skin Wound Care 2011;24:78-84.
6. To E, Dyck R, Gerber S, Kadavil S, Woo KY. The effectiveness of topical polyhexamethylene
biguanide (PHMB) agents for the treatment of chronic wounds: a systematic review. Surg
Technol Int 2016;XXIX:45-51.
7. Hurlow J. The benefits of using polyhexamethylene biguanide in wound care. Br J Community
Nurs 2017;22(Suppl 3):S16-8.
8. Kirker KR, Fisher ST, James GA, McGhee D, Shah CB. Efficacy of polyhexamethylene
biguanide–containing antimicrobial foam dressing against MRSA relative to standard foam
dressing. Wounds 2009;21(9):229-33.
9. Leaper D. Appropriate use of silver dressings in wounds: international consensus document. Int
Wound J 2012;9(5):461-4.
10. Munter KC, Beele H, Russell L, et al. Effect of a sustained silver-releasing dressing on
ulcers with delayed healing: the CONTOP study. J Wound Care 2006;15(5):199-206.
11. Carter MJ, Tingley-Kelley K, Warriner RA. Silver treatments and silver-impregnated dressings
for the healing of leg wounds and ulcers: a systematic review and meta-analysis. J Am Acad
Dermatol 2010;63:668-79.
12. O_Meara S, Al-Kurdi D, Ologun Y, Ovington LG, Martyn-St James M, Richardson R. Antibiotics
and antiseptics for venous leg ulcers. Cochrane Database Syst Rev 2014;(1):CD003557.
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8(6):547-9.
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Syst Rev 2014;(5):CD003948.
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site infection. Cochrane Database Syst Rev 2014;(9):CD003091.
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for pressure ulcers. Cochrane Database Syst Rev 2016;4:CD011586.
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with an antibacterial foam dressing bound with gentian violet and methylene blue. Adv Skin
Wound Care 2014;27(3 Suppl 1):9-13.
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for management of chronic wounds with local infection [published online ahead of print
May 16, 2017]. Int Wound J 2017.
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26. Khadanga S, Dugar D, Karuna T, et al. Effects of topical honey dressing in decubitus
ulcer. Asian J Med Sci 2015;6(4).
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